Molecular mechanisms involved in the process of muscle wasting : human and animal studies

Abstract

Muscle dysfunction and muscle wasting are major systemic manifestations of chronic conditions such as Chronic Obstructive Pulmonary Disease (COPD) and cancer. Several biological mechanisms contribute to such a dysfunction. Our objectives were to identify cellular and molecular mechanisms involved in the respiratory and peripheral muscle dysfunction of cachexia models associated with chronic respiratory conditions. The diaphragm and gastrocnemius of mice [emphysema and lung cancer (LC) models] and the vastus lateralis of severe COPD patients were studied with their respective healthy controls. Muscle structure was analyzed in the animal LC model and in the COPD human model. Several biological markers were studied: proteolysis markers, signaling pathways related to proteolysis, redox balance and inflammation. Mitochondrial respiratory chain was also explored in the LC mice model. In all three models the cachectic subjects were identified using total body weight. In patients, fat-free mass index was also identified. In the mouse models, muscle weights were also determined. They were decreased in all cachectic animals compared to the controls. Muscle structure was affected in the cachectic subjects: LC cachectic mice showed a decrease in both type I and II fibers size, while muscle-wasted COPD patients showed a decrease in type II fiber sizes and in proportions of type I fibers. Proportions of myofiber abnormalities were greater in both LC cachectic animals and muscle-wasted COPD patients. Only LC cachectic mice showed higher levels of IFNγ in the diaphragm. Oxidative stress, proteolysis markers and NFκB pathway were enhanced in the muscles of the cachectic subjects in the three models. Mitogen-activated protein kinases (MAPK) and forkhead box (FoxO) signaling pathways were enhanced in the muscles of the cachectic mice. Myogenin levels were reduced in the muscles of all three models. Myostatin levels were greater in the muscles of the cachectic mice. Mitochondrial function was depressed in both respiratory and limb muscles of the LC cachectic mice. We conclude that enhanced protein catabolism and mitochondrial dysfunction occurs in the muscles of these cachexia models (both patients and animals). Major signaling pathways such as NF-kB and FoxO are involved in this process. These findings offer future therapeutic strategies in cachexia associated with chronic respiratory conditions.